Morphine and other opiates act as powerful analgesics [Foye, W. O. in “Principles of Medicinal Chemistry,” Third Edition, Lea & Febiger, Philadelphia, 1989]. Considerable effort has been put forth to develop and understand the appropriate use of narcotic analgesics for terminal patients and for easing the pain of cancer, yet new medications are greatly needed. Morphine elicits a number of pharmacological activities mediated by mu opioid receptors, including analgesia, respiratory depression, and inhibition of gastrointestinal transit. [See O. Ray, “Drugs, Society and Human Behavior,” Third Edition, The C. V. Mosby Co., St. Louis (1983)]. However, adverse side effects and the abuse potential have limited morphine availability and optimal use. Solubility and potency issues limit the amount of injectable morphine as well. There is a need for longer-lived agents for severe pain. There is a need for agents that do not need to be administered by expensive i.v. or epidural routes of administration. There is also a need for medications that do not cause respiratory depression, tolerance, urinary retention, constipation, physical dependence, and/or addiction. In addition, some of the existing pain conditions are resistant to the analgesic action of currently available opiates. There is also a need for effective analgesics that only work in the periphery and do not enter the brain.
Tolerance is defined as a reduced sensitivity to the effect of an opiate and generally indicates an attenuation in analgesic efficacy causing dependence revealed by the physical manifestations of withdrawal. [See B. L. Kieffer et al., Cell, 108:87-90 (2002).] Tolerance is almost exclusively associated with analgesia. It has been long thought that tolerance is caused by a reduction in surface receptors and opioid receptor signaling. However, morphine does not promote efficient mu receptor internalization, [see J. L. Whistler et al., Neuron, 23:737-46 (1999)] whereas other opioids such as the mu-selective peptide DAMGO and the alkaloid fentanyl do promote such internalization. In vitro models show that DAMGO administered at concentrations below the threshold for inducing internalization can induce internalization of the mu receptor in the presence of morphine. [See L. He et al., Cell, 108:271-82 (2002).] Analgesia following continuous administration of morphine is markedly enhanced when a sub-internalizing dose of DAMGO is co-administered to rats. [See L. He et al., supra.] This link between mu receptor internalization on the cellular level and tolerance in vivo suggests that receptor internalization may provide protection against tolerance. Determining which analogs of M6G effect receptor internalization may therefore be an important step to developing a non-addictive analgesic and furthering our understanding of the addiction process. Development of antagonists of the mu, delta, or kappa receptor also result in useful medications. Replacement of the N-17 methyl group in these M6G analogs with other alkyl, cycloalkyl and alkenyl groups could provide pharmacologically active antagonists at the opioid receptors. Such antagonists could be useful in treatment of diseases of the CNS including drug addiction, gambling addiction, and alcoholism. Elaboration of a derivative that is constantly charged and contains a quaternary amine or a guanadino group could also provide a new set of analgesics that only work in the periphery.
A major pathway for removing morphine and related opiates from the body is through the formation of water soluble glucuronide conjugates in the liver and subsequent excretion in the urine. In the case of morphine, three glucuronides are formed: morphine-6-β-D-glucuronide, morphine-3,3-D-glucuronide and morphine-3,6-di-β-D-glucuronide. Morphine-6-O-D-glucuronide (M6G) is an analgesic with a potency 100-fold greater than morphine itself. [See G. W. Pasternak, Life Sci., 41:2845-2849 (1987).] The low bioavailability (11%) of M6G due to hydrolysis in the gut by stomach acid is a significant limitation in the development of a drug from this compound. [See R. T. Penson et al., Br. J. Clin. Pharmacol., 53:347-354 (2002).] Development of new medications based upon M6G is promising because of its analgesic potency, favorable side effect profile, and distinct pharmacological activity. [See M. H. Hanna et al., Anesthesiology, 102:815-821 (2005).]
Glucuronides as a rule are thought to be highly polar metabolites and unable to cross the blood brain barrier (BBB). [See G. W. Pasternak, Clin. Neuropharmacol., 16:1-18 (1993).] However, M6G is apparently much more lipophilic than predicted. [See P. A. Carrupt et al., J. Med. Chem., 34:1272-1275 (1991).] Polar surface area (PSA) calculations suggest molecules above 90 Å2 do not get into the brain. [See K. Palm et al., J. Pharm. Sci., 85:32-39 (1996a).] For BBB penetration via the transcellular route a molecule should have a MW of <450 and a PSA<90 Å2. Related calculations show that oral absorption is optimal with a PSA<120 Å2. [See J. Kelder et al., Pharmaceutical Research, 16:1514-1519 (1999).] In rats, after oral administration, M6G was absorbed per se in the proximal intestine, showing that M6G is capable of membrane penetration. [See R. Stain-Texier et al., Drug Metab. Dispos., 26:383-387, (1998).] But analogs of M6G with a molecular weight greater than 450 are predicted to not get into the brain, and because of the more polar nature compared to morphine, are predicted by others to not have more favorable CNS biodistribution and onset of action properties.